WO2005044759A2 - Acetalisation pour preparation de composes steroides - Google Patents

Acetalisation pour preparation de composes steroides Download PDF

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Publication number
WO2005044759A2
WO2005044759A2 PCT/IN2004/000239 IN2004000239W WO2005044759A2 WO 2005044759 A2 WO2005044759 A2 WO 2005044759A2 IN 2004000239 W IN2004000239 W IN 2004000239W WO 2005044759 A2 WO2005044759 A2 WO 2005044759A2
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WIPO (PCT)
Prior art keywords
formula
compound
preparation
substituted
budesonide
Prior art date
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PCT/IN2004/000239
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English (en)
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WO2005044759A3 (fr
Inventor
Kanaksinh Jesingbhai Jadav
Trinadha Rao Chitturi
Rajamannar Thennati
Original Assignee
Sun Pharmaceutical Industries Limited
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Publication of WO2005044759A2 publication Critical patent/WO2005044759A2/fr
Publication of WO2005044759A3 publication Critical patent/WO2005044759A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms

Definitions

  • the present invention relates to a process for the preparation of 16,17-acetals of pregnane derivatives represented by a compound of formula 1. More specifically the present invention relates to a process for preparation of compound of formula 1 by reaction of 16,17-dihydroxy compound of formula 2,
  • Formula 1 Formula 2 with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid.
  • the present invention particularly relates to a process for the preparation of 16,17-acetals of formulae 5, 6, 7 or 8, namely, budesonide, ciclesonide, rofleponide and triamcinolone acetonide, respectively.
  • the compounds of formula 1 are pharmacologically active compounds or are useful as intermediates for preparation of other active compounds.
  • United States Patent No. 3929768 discloses unsymmetrical 16,17-alkylenedioxy steroids including budesonide, which are prepared by reacting the 16,17-dihydroxy compounds with aldehydes in dry dioxane solvent in presence of perchloric acid. In this process large excess of toxic solvent like dioxane (150 vols) and methylene chloride (1000 vols) has been used and the crude product is purified by column chromatography to obtain isomeric mixtutres, R/S ratio not specified.
  • Patent Nos. 4835145 disclose a process for preparation of 16,17-acetals of pregnane derivatives from the corresponding 16,17- acetonides by reaction with aldehydes in aqueous HF or HC1 acid.
  • Example 1 of the ' 145 patent exemplifies preparation of budesonide from desonide by reaction with butyraldehyde in HF acid (10 vols) wherein 22R isomer is formed predominantly.
  • Hydrofluoric acid is a highly corrosive chemical and requires special equipment, poses environmental problems.
  • United States Patent No. 6169178 relates to a process for the preparation of budesonide and of 16,17 acetals of pregnane derivatives structurally correlated thereto, comprising treating 16,17-diols, or of 16,17-ketals or cyclic acetals with aldehydes, in the presence of aqueous hydrobromic acid or hydriodic acid, used as reaction catalysts and solvents.
  • European patent application EP 0994119 Al discloses a stereoselective process for preparation of 22R epimer of budesonide by reaction of 9 ⁇ -iodo budesonide or 9 ⁇ -bromo budesonide with butyraldehyde in the presence of aq HBr or HI.
  • United States Patent No. 5556964 discloses a process for preparation of budesonide by reacting 16 ⁇ -hydroxyprednisolone in acetonitrile in the presence of p-toluene sulfonic acid as a catalyst.
  • United States Patent No. 5310896 discloses preparation of budesonide via novel formyloxylated desonide intermediate compounds by reacting with butanal in the presence of a strong acid catalyst, preferably perchloric acid or fluroboric acid in a halogenated solvent.
  • a strong acid catalyst preferably perchloric acid or fluroboric acid in a halogenated solvent.
  • the PCT application WO 92/11280 discloses a method for preparation of (22R) epimer of budesonide by condensation reaction between ll ⁇ ,16 ⁇ ,17 ⁇ ,21-tetrahydroxy-l,4- pregnadiene-3,20-dione-21 -acetate with butyraldehyde in 70-80% HF acid.
  • United Kingdom Patent No. GB 1469575 discloses a method for preparation of 16,17- acetals or ketals of 9 ⁇ -halosteroids of the pregnane series by reacting 16,17-dihydroxy- 9,11-epoxy pregnane derivatives with aldehyde or ketone in aqueous hydrogenhalide such as 40-70% HF or 20-37% HC1 acid.
  • United States Patent No. 5750734 teaches preparation of 16,17-acetals of pregnane derivatives such as compound of formula I by transacetalization of the corresponding 16, 17-acetonides represented by compound of formula 9, by using sulphuric acid or
  • the present invention provides an acetalization process for the preparation of 16,17- acetals of pregnane derivatives of formula 1 by reaction of 16,17-dihydroxy compound of formula 2 with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid.
  • the process of the present invention involves use of phosphoric acid, which is environmentally safer and involves simple work-up and avoids the use of toxic chlorinated solvents/clioxane etc.
  • the process of the present invention provides a 16,17-acetal of a pregnane derivative such as budesonide, a compound of formula 5 in the epimeric ratio of R/S almost 1 : 1 directly which conforms to pharmacopoeial specifications of British Pharmacopoeia.
  • the present invention provides a process for the preparation of 16,17-acetals of pregi derivatives of compound of formula I
  • Rt is H, C 1 -C12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
  • R 2 is C 1 -C1 2 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted; X is OH, CI, F or -OCOR group wherein R represents H or C ⁇ -C 12 linear, branched or cyclic alkyl group that may be substituted; aryl or hetroaryl group that may be substituted;
  • R 3 is H, F or CI; .
  • R ⁇ is H, F or methyl;
  • R 5 is H 3 CI or methyl; comprising reacting the compound of formula 2, wherein the substituents are as defined R4 Formula 2 above, with a carbonyl compound of formula 3 or an acetal of formula 4 in phosphoric acid, wherein Re is Ct-C ⁇ alkyl and other substituents are as defined above.
  • the present invention provides a process for the preparation of 16 ⁇ ,17 ⁇ - butylidenedioxy-l l ⁇ ,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of formula 5
  • Formula 5 comprising reacting 16 ⁇ -hydroxyprednisolone, a compound of formula 10, Formula 10 with butyraldehyde in phosphoric acid.
  • the present invention provides acetalization process for preparation of 16,17-acetals of pregnane derivatives from corresponding 16,17-dihydroxy compounds in phosphoric acid.
  • the acetalization reaction may conveniently be effected at a temperature within the range of about -10°C to about 50°C, and preferably at about 0°C to about 5°C.
  • the acetalization reaction may conveniently be effected with the ratio of compound of formula 2:phosphoric acid being between the range of 1 :2 to 1:15, preferably between the range of 1 :3 to 1:5 wt/v.
  • the process of the present invention may be conveniently effected using commercial (about 85% w/w) phosphoric acid.
  • the compounds of formula 2 are known compounds and are commercially available or may be prepared according to known methods.
  • the present invention particularly relates to a process for the preparation of 16,17-acetals of formulae 5, 6, 7 or 8, namely, budesonide, ciclesonide, rofleponide and triamcinolone acetonide, respectively, by reacting the appropriately substituted compound of formula 2 with an appropriately substituted compound of formulae 3 or 4 in phosphoric acid.
  • the compound of formula 5 or the compound of formula 8 can be prepared;
  • the compound of formula 6 can be prepared;
  • by reacting the appropriately substituted compound of formula 6 can be prepared; by reacting the appropriately substituted compound of formula 2 with acetone, the compound of formula 7 can be prepared.
  • the present invention provides a process for the preparation of 16 ⁇ ,17 -butylidenedioxy-ll ⁇ ,21-dihydroxypregna-l,4-diene-3,20-dione, a compound of formula 5
  • the product can be isolated by dilution with aqueous solvent such as aqueous methanol and filtration/centrifugation.
  • aqueous solvent such as aqueous methanol and filtration/centrifugation.
  • the present invention provides a process for preparation of 16 ,17 ⁇ -butylidenedioxy-l l ⁇ ,21-dihydroxypregna-l 3 4-di ' ene-3,20-dione, a compound of formula 5 comprising reaction of 16 ⁇ -hydroxyprednisolone, a compound of formula 10, with butyraldehyde in phosphoric acid at temperature of about 0°C to about 5°C.
  • the mole ratio of the compound of formula 10:butyraldehyde may be between the range of 1 : 1.25 to 1 : 5, preferably 1:1.5 to 1:3.
  • the compound of formula 5 is formed in the epimeric ratio R:S between the range of 60:40 to 50:50, preferably between the range of 53:47 to 58:42.
  • the compound of formula 5 is formed in the R:S epimeric ratio of about 55:45, which conforms to British Pharmacopoieal specifications.
  • the crude budesonide was dissolved in ethyl acetate-methanol mixture (4:1, 110ml) by heating at 60-65°C. Charcoal (lg) was added and stirred at 45-55° C for 1 hr. The charcoal was filtered, and 76ml of solvent mixture was distilled out from the filtrate under atmospheric pressure. The resulting slurry was cooled to 5 to 10° C and stirred at this temperature for 1 hour. The crystallized product was filtered, washed with ethyl acetate (10ml) and dried in an air oven at 55-60° C to obtain pure budesonide (Yield 9.5g, 83.3% overall, purity 99.75%, R/S ratio 54.6:45.4). The product meets specifications as per BP, as well as purity requirements as per ICH guidelines.
  • the crude budesonide was dissolved in ethyl acetate-methanol mixture (4:1, 500ml) by heating at 60-65°C Intel Recovered 357ml of solvent mixture from the solution under atmospheric pressure. The resulting slurry was cooled to 0 to 5° C and stirred at this temperature for 1 hour. The crystallized product was filtered, washed with ethyl acetate (100ml) and dried in an air oven at 55-60° C to obtain pure budesonide (purity 99.83%, R/S ratio 57.4:42.6). The product meets specifications as per BP, as well as purity requirements as per ICH guidelines.
  • the crude budesonide (20g) obtained as above was dissolved in ethyl acetate -methanol (4:1, 240ml) by heating at reflux. The hot solution was filtered, concentrated (to about 60ml) at atmospheric temperature, and cooled to 5-10° C. The crystallized product was filtered, washed with ethyl acetate (20ml) and dried in air oven at 55-60° C. Recovery 15.9g (overall purified yield 78.4%), purity 99.62%, ratio of R/S epimers, 57.06: 42.94).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

La présente invention concerne un processus d'acétalisation permettant d'obtenir des 16, 17-acétals de dérivés de 16,17-prégnane à partir de composés 16,17dihydroxy dans de l'acide phosphorique.
PCT/IN2004/000239 2003-08-14 2004-08-10 Acetalisation pour preparation de composes steroides WO2005044759A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN810MU2003 2003-08-14
IN810/MUM/2003 2003-08-14

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WO2005044759A2 true WO2005044759A2 (fr) 2005-05-19
WO2005044759A3 WO2005044759A3 (fr) 2005-08-11

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009117120A1 (fr) * 2008-03-18 2009-09-24 Sicor Inc. Purification de stéroïdes sensibles à l’air
CN101717428B (zh) * 2009-12-15 2012-11-21 浙江工业大学 一种布地奈德的合成方法
WO2013124395A1 (fr) 2012-02-23 2013-08-29 Boehringer Ingelheim International Gmbh Nouveau procédé de préparation du ciclésonide
CN103275168A (zh) * 2013-05-27 2013-09-04 浙江仙琚制药股份有限公司 一种布地奈德的制备方法
AU2008331187B2 (en) * 2007-11-30 2014-04-03 Pfizer Limited Novel glucocorticoid receptor agonists
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL109983B1 (en) * 1976-06-10 1980-06-30 Inst Przemyslu Farmaceutic Method of producing 6-alpha-fluoro-16 alpha,17 alpha-isopropylidenodioxy-21 hydroxy-4-pregnen-3,20-dione
US5750734A (en) * 1994-11-26 1998-05-12 Rhone-Poulenc Rorer Limited Process for the preparation of steroid derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL109983B1 (en) * 1976-06-10 1980-06-30 Inst Przemyslu Farmaceutic Method of producing 6-alpha-fluoro-16 alpha,17 alpha-isopropylidenodioxy-21 hydroxy-4-pregnen-3,20-dione
US5750734A (en) * 1994-11-26 1998-05-12 Rhone-Poulenc Rorer Limited Process for the preparation of steroid derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CASREACT [Online] VIJAYKUMAR DANGE ET AL: 'An Efficient Route for the Preparation of a 21-Fluoro Progestin-16a-17a-Dioyolane, a High-Affinity Ligand for PET Imaging of the Progesterone Receptor.' Retrieved from STN Database accession no. (137:155098) & JOURNAL OF ORGANIC CHEMISTRY. vol. 67, no. 14, 2002, pages 4904 - 4910 *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008331187B2 (en) * 2007-11-30 2014-04-03 Pfizer Limited Novel glucocorticoid receptor agonists
US8822439B2 (en) 2007-11-30 2014-09-02 Pfizer Inc. Glucocorticoid receptor agonists
WO2009117120A1 (fr) * 2008-03-18 2009-09-24 Sicor Inc. Purification de stéroïdes sensibles à l’air
CN101717428B (zh) * 2009-12-15 2012-11-21 浙江工业大学 一种布地奈德的合成方法
WO2013124395A1 (fr) 2012-02-23 2013-08-29 Boehringer Ingelheim International Gmbh Nouveau procédé de préparation du ciclésonide
CN103275168A (zh) * 2013-05-27 2013-09-04 浙江仙琚制药股份有限公司 一种布地奈德的制备方法
US10668167B2 (en) 2016-06-02 2020-06-02 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof
US10772970B2 (en) 2017-12-01 2020-09-15 Abbvie Inc. Glucocorticoid receptor agonist and immunoconjugates thereof

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Publication number Publication date
WO2005044759A3 (fr) 2005-08-11

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